Tristetraprolin (TTP) Expression is Required for Mammary Progenitor Cell Survival

Micaela Stedile¹, Inés Beckerman¹, Martín García Solá¹, María Victoria Goddio¹, Lourdes Pérez Cuervo¹, Ana Raimondi¹, Edith Claudia Kordon¹


Messenger RNA (mRNA) stability is regulated by proteins that bind to their 3´untranslated regions. One of them, Tristetraprolin (TTP), coded by Zfp36 gene, produces mRNA degradation of proteins involved in inflammation and tumorigenesis. We have previously proved that Wap-Cre x TTPfl/fl mice display apoptosis of mammary epithelial cells in which Zfp36 had been deleted during lactation. Here, we show that parity-induced mammary epithelial progenitor cells are particularly affected in those bi-transgenic females, since they display underdeveloped alveoli in their second lactation. Besides, multiparous females WAP-Cre x TTPfl/fl crossbred with RasG12D+/- mice presented fewer pre-neoplastic lesions than RasG12D+/- controls. Supporting the relevance of TTP expression in undifferentiated mammary cells, mRNA-seq data assessment indicates that progenitor populations display higher levels of Zfp36 than differentiated cells. Moreover, stem-like HC11 mammary cell line stably transfected with TTP-shRNA, exhibited decreased capacity to form mammospheres (MS) and to repopulate cleared fat pads. This phenotype was associated with high expression of pro-inflammatory cytokines as well as p38, NFkB, STAT3 and Caspase 3 activation. We also found that MS formation capacity was increased blocking TNFα or inhibiting p38 phosphorylation. In summary, our results indicate that TTP plays a relevant role in mammary progenitor cell survival, by keeping in line stress-associated pathways.